This invention relates to the use of the combination of α-lipoic acid and effectors of the glutathione metabolism for the treatment of disruptions of the cellular thiol status and related illnesses.
The precise regulation of the thiol disulfide status represents one of the most important basic requirements of biological metabolisms. The central regulating element within this system is the tripeptide glutathione, which reaches high intracellular concentrations (up to 10 mM) in reduced form. In addition to glutathione, protein groups carrying thiol groups intracellularly and particularly in cell-membrane-bonded form are additional important components of the thiol disulfide status of each cell.
The metabolism of the breakup of disulfide and the formation of the thiol groups, which is regulated by various classes of enzymes, is essential for any normal cell function as a result of the variety of the biological functions of thiol in, among other things, cell growth and differentiation processes including programmed cell death as well as cell protection and decontamination mechanisms overall. Disruptions in this system and changes in the concentration of thiol lead to serious disruptions in cell function, which remain locally limited only in isolated cases, and generally have an adverse effect on the entire organism.
The involvement of a disrupted thiol disulfide status in acute and chronic diseases has been demonstrated in a number of experiments.
In neurodegenerative diseases such as Parkinson's Disease, for example, significant changes in the thiol metabolism have been demonstrated in certain nerve cells (Brain Res Rev 1997; 25:335-358). There are clear indications that as a result of this metabolic disruption, there is an increased death of nerve cells in the functionally impaired areas of the brain, the basal ganglia, which is primarily responsible for the symptoms of the disease (Ann Neurol 1994; 36:348-355).
Reduced glutathione levels and a reduced intracellular glutathione content have also been found in the context of angiopathies and their consequences—arteriosclerosis and heart attack—in the endothelial cells that line the inner wall of the vessel. (Med Sci Res 1998:26:105-106).
Pulmonary diseases that involve a transformation of the pulmonary tissue are regularly connected with a glutathione deficit in the tissue. In a pulmonary fibrosis of this type, the severity of the disease runs parallel to the thiol loss (Chin Chim Acta 1997; 265:113-119). Serious inflammatory pulmonary diseases, investigated using the example of acute difficulty of breathing in adults, were accompanied by a dysregulation of the thiol metabolism of the participating inflammatory cells (granulocytes) (Chest 1996; 109:163-166).
On the basis of the author's own tests, the immuno-competent defensive cells of the 15 bronchial system (alveolar macrophages) in smokers and in patients with chronic obstructive respiratory diseases exhibit a serious cellular thiol deficit. The severity of the disruption of the cellular thiol status is thereby directly correlated with restrictions in lung function (Free Radic Biol Med 2000; 29:1160-1165).
Extensive research into the significance of the glutathione metabolism in viral infections has revealed both a poorer prognosis of thiol-deficient cells based on a compromised cellular defense, as well as an antiviral function of the glutathione that combats the reproduction of the virus (Proc Natl Acad Sci USA 1997; 94:1967-1972).
The author's own tests have shown that the cellular thiol disulfide metabolism is seriously disrupted, particularly under the conditions of severely restricted kidney function and the resulting necessary renal replacement therapy in the form of hemodialysis or peritoneal dialysis. This disruption results in, among other things, the extensive loss of normal cell functions, such as the phagocytosis capability of peritoneal macrophages or the activation of lymphocytes.
The human cellular immune system, which consists of the white blood cells granulocytes, lymphocytes and monocytes, represents a system that reacts particularly sensitively to a disruption in the thiol metabolism.
Minimal changes, particularly losses of cellular glutathione, can trigger a cascade-like program for the self-destruction of the cells, the programmed cell death (apoptosis) (FASEB J 1998; 12:479-486). In this case, the thiol disulfide metabolism acts as a central switching mechanism of an intact immune system, without which the organism would not be viable.
In recent years, moreover, there have been increasing references to a damaged thiol metabolism in chronic kidney diseases (Ren Fail 1998; 20:1 17-124), anemias (Br J Haematol 1995; 91:811-819), premature newborns (Pediatr Pulmonol 1995; 20:160 166), hearing loss caused by noise (Brain Res 1998; 784:82-90), inflammatory bowel diseases (Gut 1998; 42:485-492) and particularly in diabetes mellitus (Metabolism: Clinical and Experimental 1998; 47(8):993-997).
Studies in the context of diabetes mellitus and associated metabolic disruptions have demonstrated both a shift of the redox status at the expense of reduced glutathione as well as an absolute reduction of the total glutathione pool (Free Radic Biol Med 1998; 24:699-704). In the summary of the previous literature on the role of the disruption of the thiol disulfide status, it has been assumed that not only is there an accompanying SH deficit as a consequence of the primary disease, which is Type 1 or Type 2 diabetes, but that a dysregulation in the thiol metabolism is at least one factor that triggers the disease. A convincing example has been provided, among other things, by the verification of the radical-induced destruction of the pancreatic B-cells (Diabet Med 2000; 17:171-180).
It is also known that the disease is accompanied by a number of immunological disruptions. The primary factor that has been identified is an imbalance of the immunoregulator cytokine, which is related to functional disruptions of the lymphocytes and macrophages, with a resulting significant increase in the sensitivity of the patients to infections (Horm Metab Res 1998; 30:526-530).
The correction of a disrupted thiol metabolism thus acquires fundamental importance as a basic therapy in the treatment of a number of diseases of different geneses, particularly, however, under the conditions of diabetes mellitus.
α-lipoic acid has been used relatively successfully in the form of a neuro-protective substance for the treatment of neuro-toxically caused paresthesia in the context of diabetic polyneuropathy (Diabetologica 1995; 38: 1425-1433, Diabetes Res Clin Pract 1995; 29:19-26, Diab Care 1999; 22:1296-1301, Drug Metab Rev 1997; 29:1025-1054, DE 43 43 592 C2). DE 44 47 599 C2 and EP 0 530 446 B1 also describe the use of α-lipoic acid in additional neuronal disruptions, including tinnitus and apoplectiform deafness.
In this case, the cytoprotective mechanism of action depends on the influence of the sugar-dependent protein modification (protein glycolysis), on a reduction of neurotoxic ketogenesis, and finally on the anti-oxidation function of the α-lipoic acid and its metabolites (Free Radic Biol Med 1995; 19:227-250).
This cell protection function has been investigated particularly from the point of view of the prevention of the oxidative transformation of essentially unsaturated fatty acids. Such an inhibition of the lipid peroxidation, in addition to the use of the α-lipoic acid as a neuro-protection agent, represents the basis for an application as a medicament to protect the liver in the treatment of various intoxications and liver diseases (Biochemistry 1998; 37:1357-1364).
It has also been shown that α-lipoic acid inhibits the reproduction of the HIV virus in different stages of its growth and may thus counteract a progression of the AIDS disease. The results of these laboratory tests can be applied to clinical studies only to a limited extent, however (FEBS-Lett 1996; 394:9-13). The same is true for the detection of an anti-inflammatory function of the substance for the insulin-producing islet cells of the pancreas (Agents Actions 1993; 38:60-65).
EP 0 812 590 A2 and EP 0 427 247 B1 disclose the use of α-lipoic acid as a cyto-protective, as an analgesic and as a medicament for the treatment of inflammatory diseases.
The anti-oxidative properties of α-lipoic acid are based on its ability to form chelates with metal ions and to eliminate radicals directly, as well as on its function as a strong reducing agent. To perform this reaction on an intracellular level, α-lipoic acid, even in reduced form, must be present in the form of dihydrolipoic acid. The transition from (disulfide) α-lipoic acid by means of reduction into the dithiol form of dihydrolipoic acid for its part consumes reducing equivalents, whereby this process is catalyzed by, among other things, the enzyme glutathione reductase (Gen Pharmacol 1997; 29:315-331). This process is apparently the cause of the unsatisfactory action of the substance in terms of thiol restitution.
Ambroxol, i.e. trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexane hydrochloride, is administered in various forms as an expectorant in the treatment of pulmonary and bronchial diseases (WO 96 33704, GB 2239242, WO 01 05378). Its use in the treatment of hyperuricemia is also known from DE 35 30 761. The action of ambroxol as a mucolytic is based both on a stimulation of surfactant production by the bronchial cells and particularly on its ability to eliminate free radicals (Respir Med 1998; 92:609-23). The anti-oxidative activity of the substance based on these properties was demonstrated primarily on pulmonary cells (Pharmacol 1999; 59:135-141), but also in the context of inflammatory mechanisms (Inflamm Res 1999; 48:86-93). It is also known that through the use of ambroxol in high doses, enzymes that regulate the glutathione metabolism can be influenced directly and peroxidative processes can be inhibited in vitro (Arch Vet Pol 1992; 32:57-66).